Enhanced brain bioavailability of galantamine by selected formulations and transmucosal administration of lipophilic prodrugs

ABSTRACT

A method of treating a subject for a brain disease associated with cognitive impairment, including administering to a subject a chemical substance according to GLN-1062 or salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein the GLN-1062 or salt thereof is in a multi-layered tablet with a digestive acid resistant coating.

The invention relates to selected administration routes for CNS (centralnervous system) therapeutics and highly soluble salts, solutions,emulsions or powder formulations thereof, having optimal brain deliverydue to the mode of administration and the chemical nature of thecompounds of the invention. The therapeutic compounds of the presentinvention relate to lipophilic pro-drugs of pharmacologically activecompounds that—as prodrugs—are inactive in regard to their major targetsin the CNS, in particular cholinesterases and/or nicotinic acetylcholinereceptors. Via cleavage by endogenous enzymes, the pharmacologicallyactive parent drugs are produced and act as allosterically potentiatingligands (APL) on nicotinic acetylcholine receptors (nAChR), and/or asreversible inhibitors of acetylcholinesterases (AChE) and othercholinesterases (ChE). To maximize transport through the blood-brainbarrier (BBB) and in order to protect the prodrugs of the invention fromcleavage by endogenous esterases before crossing the BBB to theirsite(s) of action, the pro-drugs are designed to be highly lipophilic(log P>2.5) and are delivered via transmucosal absorption pathways inthe oral or nasal cavity.

BACKGROUND OF THE INVENTION

Currently, the first line of drug treatment for Alzheimer's disease (AD)is the use of cholinesterase inhibitors, such as donepezil, rivastigmineand galantamine. Among these, galantamine has been shown to have adistinct second mode of action, i.e. allosterical sensitisation ofnicotinic acetylcholine receptors (Maelicke A; Albuquerque E X (1996)New appoaches to drug therapy in Alzheimer's dementia. Drug DiscoveryToday 1, 53-59). Galantamine enhances the probability of channel openinginduced by submaximal concentrations of acetylcholine (ACh), or choline(Ch), or other nAChR agonists. Because progression of AD is associatedby an increasing loss of nAChR, the APL-enhanced activity of nicotinicreceptors is a suitable symptomatic and possibly also disease-modifyingtreatment for AD and other forms of dementia (Storch A et al. (1995).Physostigmine, galantamine and codeine act as noncompetitive nicotinicagonists on clonal rat pheochromocytoma cells. Eur J Biochem 290:207-219; Kihara T et al. (2004) Galantamine modulates nicotinicreceptors and blocks AB-enhanced glutamate toxicity. Biochem Biophys ResCommun 325: 976-982; Akata K et al. (2011) Galantamine-inducedamyloid-clearance mediated via stimulation of microglial nicotinicacetylcholine receptors. J Biol Chem 286; Maelicke A (2006) Allostericsensitisation of brain nicotinic receptors as a treatment strategy inAlzheimer's dementia. In: Therapeutic Strategies in Dementia (Eds:Ritchie C W, Ames D J, Masters C L, Cummings J), Clinical Publishing,Oxford, 2006; 153-172)).

In contrast to rivastigmine and donepezil, galantamine does notsignificantly enrich in the human brain in comparison to blood plasma.This is because galantamine, being a plant alkaloid rather than arationally designed drug, is much less lipophilic than the other twocholinesterase inhibitors used as drugs in AD and hence exhibits insteady-state only a rather low brain-to-blood concentration ratio(BBCR<2).

To enhance the lipophilicity of CNS drugs and their passage through theblood-brain barrier, hydrophobic side chains have been appended to thebasic alkaloid structures, as described in EP1 940 817 B1 and WO2009/127218 A1. The attached groups were selected in order to increasethe BBRC to larger than 5.

Similar to other cholinesterase inhibitors, galantamine has a clinicallysignificant level of mechanism-based gastro-intestinal (GI) sideeffects, including nausea, vomiting and diarrhea (Loy C et al.,Galantamine for Alzheimer's disease and mild cognitive impairment.Cochrane Database of Systematic Reviews 2006, Issue 1). To accommodatepatients to these side effects, cholinesterase inhibitors usually areinitially administered at a low (non-efficacious) dose, with the dosebeing carefully up-titrated to an efficacious one, within a period ofmonths. Moreover, the maintenance dose often is adjusted to what thepatients experience as an acceptable level of GI side effects, making itlikely that most, if not all, patients never achieve treatment with themost effective dose. Accordingly, cholinesterase inhibitors aregenerally perceived as of only low effectiveness and as associated withunpleasant side effects. In light of the prior art regarding theadministration of galantamine, it becomes apparent that the potentialtherapeutic efficacy of galantamine has never been able to be applied inhuman subjects to its full extent due to the poor brain-to-bloodconcentration ratio and significant peripheral side effects arising frompoor brain delivery. Because galantamine is known to affect motor andevacuative function of intestinal tissue (Turiiski V I et al. (2004), invivo and in vitro study of the influence of the anticholinesterase druggalantamine on motor and evacuative functions of rat gastrointestinaltract. Eur J Pharmacol 498, 233-239), a reduction in GI side effects ofgalantamine was attempted by intranasal rather than oral administrationof the drug (Leonard A K et al. (2007), In vitro formulationoptimization of intranasal galantamine leading to enhancedbioavailability and reduced emetic response in vivo. Int J Pharmaceut335: 138-146).

Because of the limited volume of spray that can be applied in one sprayevent to each nostril, the intranasal route of administration requireshighly soluble drug product formulations. This was only in part achievedfor galantamine by replacing in the hydrobromide of the drug the bromideion by lactate or gluconate. This change in salt form did notsignificantly improve transport through the BBB of galantamine, as it isthe rather hydrophilic and polar galantamine base that is resorbed atthe nasal epithelium and then transported across the blood-brainbarrier. Because of these physicochemical limitations, galantamine andits tertiary and quarternary nitrogen salts exhibit brain-to-bloodconcentration ratios below 2, meaning that such drugs must beadministered in rather large quantities in order to achieve significantdrug levels in the target organ brain. Sufficiently effective doses inthe brain of such hydrophilic drugs are therefore achieved at theexpense of considerable levels of peripheral side effects, in particulargastro-intestinal side effects. It can be concluded that saltformulations of galantamine have not provided a satisfactory solutionfor enhancing the brain drug distribution via the BBB.

As described previously (WO2009/127218 A1), the relatively hydrophilicparent drugs of interest can be reformulated by chemical conversion tolipophilic ester pro-drugs. Alcoholic OH groups have been used forattaching aliphatic, aromatic or heteroaromatic carboxylic acids to theparent drug thereby (i) partially or fully inactivating thempharmacologically, and (ii) significantly enhancing their lipophilicityand BBB penetration.

Although ester formation is a commonly employed approach to increase thelipophilicity of polar molecules having limited BBB penetration, theabundance of nonspecific esterases in brain and peripheral tissueslimits the effectiveness of this approach in enhancing brain/plasmaconcentration ratios of drugs. To maximize brain drug levels by thepro-drug approach, the kinetics of absorption, BBB penetration andbioconversion of pro-drug to drug in the target organ brain have to besufficiently fast in order to successfully compete with elimination frombrain of the less lipophilic drug after its generation. There remaintherefore significant hurdles in the development of strategies, methodsand/or medicinal agents that allow or exhibit reliable penetration ofthe BBB and are cleaved in the target organ (brain), in order to providean enhanced amount of active substance in the brain without leading tocleavage in other organs or tissues of the body, which leads in manycases to substantial side-effects during treatment.

The possibility of intranasal administration of galantamine derivativesis disclosed in US 2009/0253654 A1. No mention is made of enhanceddelivery to the brain or of means of avoiding in vivo enzymatic cleavageby endogenous esterases of the ester prodrug compoundspost-administration. The salts and concentrations of the compoundsdisclosed in US 2009/0253654 A1 represent arbitrary disclosures withoutregard to the in vivo properties of the compounds. Neither specificsalts nor transmucosal administration routes are disclosed with respectto GLN 1062.

WO2009/127218 A1 and Maelicke et al (J Mol Neurosci, 2010, 40:135-137)disclose GLN 1062 as such and its administration in the treatment ofbrain disorders with cognitive deficit. No mention is made of particularmodes of administration or of particular salts. These earlierdisclosures are based on intravenous administration of the compoundsdisclosed therein. Such bolus injections permit very fast distributionfrom blood to other organs, including the brain, and hence reduce theprobability of enzymatic cleavage prior to reaching the BBB anddistribution to the brain. Intravenous administration is however notacceptable for daily patient self-administration. More easilyadministered but equally effective alternatives are required.

Leonard A K et al. (2007, Int J Pharmaceut 335: 138-146) disclosesintranasal administration of the lactate salt of galantamine Noparticular effect is prescribed to the use of the lactate salt. Thepolar galantamine base is resorbed at the nasal epithelium and thentransported across the blood-brain barrier, but only poorly, accordingto its limited propensity for brain drug distribution via the BBB. US2004/0254146 discloses various salts of galantamine including lactateand gluconate salts and their administration in Alzheimer's disease.Neither US 2004/0254146 nor Leonard A K et al. is relevant foradministration of salts of GLN 1062, which—due to its prodrugproperties—represents the solution to an entirely different technicalproblem when compared to galantamine.

SUMMARY OF THE INVENTION

Transmucosal routes of delivery for the compounds described herein inthe oral and nasal cavity have been examined as non-invasive routes ofpro-drug administration best suited to achieve enhanced levels of drugin the brain. For systemic drug delivery, transmucosal routes areenhanced by prodrug salt formulations that accommodate to the structureand environment of the particular absorption area.

The advantageous transport properties of the pro-drugs discussed hereincan be achieved when the pro-drugs are administered by intravenousinjections, but less well, or only to a very small extent, when they areadministered orally as tablets. This is because the pro-drugs are estersthat have now been found to be instable in acidic environment (such asexists in the stomach) and are also cleaved enzymatically in manytissues, including in the intestines and in the liver (first-passeffect). In light of these findings and the problems of theadministration methods of the prior art, and in order to take advantageof the nature of the pro-drugs in the treatment of CNS diseases, theinvention makes use of administration routes that avoid thegastro-intestinal tract and the first-pass effect. These routes providebrain delivery about as efficiently as intravenous injection, which dueto significant medical risk is normally not suited for reliableself-administration. The invention provides special pharmaceuticalformulations to be used for the selected routes of administration thatoptimize rapid resorption and uptake of prodrug into the brain.

In light of the prior art the technical problem underlying the presentinvention is to provide alternative or improved means for enhancedbioavailability of the CNS therapeutics described herein, therebyproviding effective treatment of brain diseases associated withcognitive impairment.

This problem is solved by the features of the independent claims.Preferred embodiments of the present invention are provided by thedependent claims.

Therefore, an object of the invention is to provide a chemical substanceaccording to Formula I for use as a medicament in the treatment of braindisease associated with cognitive impairment, wherein said treatmentcomprises transmucosal administration, selected from intranasal,sublingual or buccal administration, of a therapeutically effectiveamount of said substance,

wherein

R1=aromatic or heteroaromatic 5- or 6-membered ring, such as optionallysubstituted benzene, naphthaline, thiophene, pyrrole, imidazole,pyrazole, oxazole, thiazole; or straight or branched chained aliphaticresidues, such as CH(C₂H₅)CH₃, CH₂—C(CH₃)₃, cyclopropane or preferablyan aliphatic residue comprising more than 5 C atoms, more preferably 6 Catoms, or more than 10 C atoms, such as a fatty acid residue.

The invention relates therefore primarily to the use of, or a method oftreatment comprising administration of, the chemical substance asdescribed herein for the treatment of brain disease associated withcognitive impairment by administering a therapeutically effective amountof said chemical substance by a transmucosal route selected fromintranasal, buccal and/or sublingual administration.

In a preferred embodiment the chemical substance of the presentinvention is characterised in that the substance is selected fromFormula

wherein

R2-R6 comprise of any substituent selected from H, halogen, optionallysubstituted C₁-C₃ alkyl or cyclopropyl, OH, O-alkyl, SH, S-alkyl, NH₂,NH-alkyl, N-dialkyl, optionally substituted aryl or heteroaryl, wherebyneighbouring substitutents can cooperate to form an additional ring.

The optional substitution of the substituents described in Formula I andII relates to substitution with an alkyl, OH, halogen, NH₂, alkyl-NH₂ orNO₂ group, or other substituent described with regard to those compoundsprovided Table 2.

Compounds according to Formula I or II with aromatic or heteroaromatic5- or 6-member rings at the R1 position of Formula I are preferred;examples of such compounds are found in Table 2, namely GLN-1062,GLN-1081, GLN-1082, GLN-1083, GLN-1084, GLN-1085, GLN-1086, GLN-1088,GLN-1089, GLN-1090, GLN-1091, GLN-1092, GLN-1093, GLN-1094, GLN-1095,GLN-1096, GLN-1097, GLN-1098, GLN-1099, GLN-1100, GLN-1101, GLN-1102,GLN-1103, GLN-1104, GLN-1105, GLN-1113.

In a particularly preferred embodiment the chemical substance of thepresent invention is characterised in that the substance is GLN-1062,whereby GLN-1062 is represented by

The transmucosal administration of the present invention is based on theunexpected realisation that the compounds of the present inventionexhibit relatively low stability when administered via oraladministration. Cleavage of the ester group occurs in the gut and liver,in addition to other tissues of the body. The transmucosaladministration provides an enhanced transport into brain and blood andcorresponding enhanced efficacy by avoiding the first pass effect andcleavage of the prodrugs during passage through the gastro-intestinaltract and other organs.

Transmucosal administration of galantamine according to the prior artprovides no such enhancement, as galantamine is not susceptible tocleavage by endogenous esterases. The surprising concept of theinvention is based on the avoidance of cleavage of the prodrugpost-administration but before partition via the BBB, thereby enhancingbrain transport and increased relative concentration of the activesubstance after cleavage, which under conditions of the proposed routesof administration and drug formulations occurs primarily in the brain.

It was entirely surprising that the transmucosal administration of theprodrugs as described herein would lead to further enhancements in braindelivery of the prodrug and ultimately (after cleavage of the prodrug)to an effective dose of galantamine in the brain of subjects.

The invention therefore relates to a chemical substance for use as amedicament in the treatment of brain disease associated with cognitiveimpairment as described herein, wherein transmucosal administrationprovides avoidance and/or reduction of post-administration cleavage ofthe ester group of said substance by endogenous esterases.

This aspect of the invention represents a novel technical effect notpreviously disclosed or suggested in the art. The relatively lowstability of the ester moiety of Memogain in the gastro-intestinal tractand liver has not been previously described in the art. A skilled personwould therefore not have attempted to provide the modes ofadministration, or the salts as described herein, in order to improvedelivery of the uncleaved compound to the brain. As demonstrated in theexamples provide herein, the recognition of post-administration cleavageafter oral administration in form of tablets has enabled the provisionof the transmucosal administration of the invention, in addition to thesalts as described herein.

The avoidance of in vivo esterase cleavage—with regard to thesignificant improvements obtained by transmucosal administration and theenhanced delivery of the salts described herein—enables treatment ofpatients who previously have avoided treatment with ChE inhibitors dueto strong gastro-intestinal side effects associated with orallyadministered tablets. The improved brain delivery via transmucosaladministration, in particular of high concentration aqueous solutions ofMemogain salts, permits dosage regimes which were until now simply notpossible with either galantamine itself (due to significant sideeffects) or Memogain (due to in vivo degradation).

Despite showing promising effects, galantamine treatment is associatedwith low compliance (of approximately 30%) due to strong unwanted sideeffects, indicating the strong need in the field for more sustainabletherapeutic approaches. The administration routes and salts describedherein enable treatment regimes with Memogain and its active principlegalantamine that have never been achieved before, potentially enablingtreatment of severe neurodegenerative disease—in patients who previouslywere not able to be effectively treated due to unwanted sideeffects—with the means and methods of the present invention.

In a preferred embodiment the chemical substance of the presentinvention is characterised in that the chemical substance is present asa salt, preferably a lactate, gluconate, maleate or saccharate salt.

In a preferred embodiment the salt comprises of stoichiometric and/ornon-stoichiometric salts and/or hydrates of the chemical substancesaccording to Formula I, II or III, whereby the salt is preferablydescribed as:

Substance of Formula I, II or III·n HX·m H2O, whereby n, m=0-5 and n andm can be the same or different, and HX=an acid, selected preferably fromlactic acid, gluconic acid, maleic acid or saccharic acid.

The invention also relates to a chemical substance for use as amedicament in the treatment of brain disease associated with cognitiveimpairment, wherein the chemical substance is the saccharate salt of GLN1062. The saccharate salt of the present invention enables surprisinglyhigh concentrations of up to 70% in water, providing an improved stablesolution for high transmucosal doses of prodrug.

One preferred example of the invention relates to a chemical substancefor use as a medicament in the treatment of brain disease associatedwith cognitive impairment, wherein the chemical substance is thegluconate salt of GLN-1062.

The gluconate salt of GLN 1062 has a high solubility, of 40% and more inwater, especially in temperatures of around 25 to 50 degrees C. Thishigh solubility at elevated temperatures can be used to produce highconcentration liquid solutions of the gluconate salt of GLN 1062, whichis relatively stable and can be administered for some days aftercreation of the solution.

The invention also relates to a chemical substance for use as amedicament in the treatment of brain disease associated with cognitiveimpairment, wherein the chemical substance is the maleate salt of GLN1062.

The invention also relates to a chemical substance for use as amedicament in the treatment of brain disease associated with cognitiveimpairment, wherein the chemical substance is the lactate salt of GLN1062.

The salts of the present invention also additionally show the surprisingproperty of improved taste (reduced bitterness), reducing the need fortaste masking components in the composition. The salts of the inventionalso show reduced numbing effects, such are as known for galantamine,when administered transmucosally. Due to their fast and efficient uptakethe numbing (analgesic) effect and poor taste are reduced compared tothose compositions described in the art.

In one embodiment the chemical substance of the present invention ischaracterised in that the chemical substance has solubility in water ofat least 10%, preferably >20%, or more preferably >30% weight per volume(w/v).

The enhanced solubility of the salts as described herein represents asurprising and beneficial development. The solubility of the saltsdescribed herein enables higher concentrations of the compound to beadministered in smaller volumes, thereby further enhancing the directadministration to the brain via transmucosal administration as describedherein.

The transmucosal administration in combination with the salts of theprodrugs of the present invention exhibits a synergistic effect. Theenhanced solubility allows higher concentrations of chemical substanceto be administered, thereby enabling larger amounts of the activesubstance after cleavage (galantamine) to be active in the brain. Thetransport of substance (measured either by substance itself in the brainor by galantamine levels in the brain after cleavage of the prodrug) isgreater than the expected sum of effects of transmucosal administration,administration of salts and administration of the prodrug whenconsidered individually.

The prodrug properties of the compounds described herein are exploitedand enhanced in a synergistic manner by the transmucosal application oftheir salts. The transmucosal administration of salts of prodrugs (withhigh solubility) provides a unique combination of administrationparameters that enable dosage regimes previously not possible withgalantamine, or salts of galantamine.

In one embodiment the present invention is characterised in that thechemical substance is administered at a dosage of from 0.1 to 200 mg, 1to 100 mg, preferably 2 to 40 mg, preferably from one to three timesdaily, more preferably twice daily, and even more preferably only oncedaily.

The dosage regimes as described herein represent novel and surprisinglybeneficial developments in comparison to the prior art with respect toeffective galantamine treatment. The biological and medical effect ofgalantamine has never previously been tested with regard to thepotential effect generated by administration at high doses. Manypatients in need of galantamine treatment have not been able to betreated due to the significant side effects that occur with regulardoses of galantamine. In order to obtain meaningful levels ofgalantamine in the brain of subjects, the prior art teaches high butalso highly toxic doses. Because only a small fraction of orally orintranasally administered galantamine drug reaches the brain, the doserequired to show an effect during treatment of brain disease is oftenintolerably high due to the large amount of galantamine in other tissuesof the body, thereby causing unwanted side effects.

The dosages of the present invention are enabled by the transmucosaladministration of the prodrugs disclosed herein. Due to enhanced braindelivery of the hydrophobic prodrugs, in combination with furtherenhanced delivery due to transmucosal administration, smaller doses ofthe prodrug are required in order to achieve the same or greater effectof galantamine in the brain after prodrug cleavage and release of theactive compound. It is entirely surprising that also lower doses of theprodrugs of the invention, for example GLN 1062, within the ranges ofthe invention, lead to more pronounced and/or more potent effect incognitive recovery compared to oral administration of galantamine.

These dosage regimes are particularly beneficial when administered inthe form of salts of the compounds as described herein.

In one embodiment the invention relates to a chemical substance asdescribed herein for use as a medicament in the treatment of braindisease associated with cognitive impairment, wherein the chemicalsubstance or salt thereof is administered intranasally, bucally orsublingually as a 2 to 40% weight per volume (w/v) solution at an amountof 20 to 100 microliters, preferably in a single (intranasal or oral)spray event, one to three times daily.

At these doses effective cognitive recovery is possible in patients withbrain diseases with no (or only very minor) observable side effects. Itwas at the time of the invention unexpected, that through thecombination of prodrug (preferably GLN 1062) and transmucosaladministration such dosages could lead to an effective galantaminetreatment through a dosage regime comprising a relatively small numberof administration events of relatively small volumes of active compound(via sprays or administration of oral transmucosal formulations).

In one preferred embodiment the invention relates to a chemicalsubstance as described herein for use as a medicament in the treatmentof brain disease associated with cognitive impairment, wherein thechemical substance or salt thereof is administered intranasally, bucallyor sublingually as a 10% weight per volume (w/v) solution at an amountof 50 microliters, preferably in a single (intranasal or oral) sprayevent, one to three times daily.

In one embodiment the invention relates to a chemical substance asdescribed herein for use as a medicament in the treatment of braindisease associated with cognitive impairment, wherein the brain diseaseto be treated is Alzheimer's and/or Parkinson's disease, the chemicalsubstance is the gluconate or saccharate salt of GLN 1062, which isadministered intranasally, bucally or sublingually as a 2 to 40% weightper volume (w/v) solution at an amount of 20 to 100 microliters,preferably in a single (intranasal or oral) spray event, one to threetimes daily.

The salt formulations of GLN 1062 show surprisingly high solubility,allowing high doses of GLN 1062 to be applied with ease by the patientsthemselves in small volumes, providing therapeutically relevant resultswithout the need for much higher doses of the prodrugs or their activeparent drug galantamine and without the occurrence of significant sideeffects.

In one embodiment the invention relates to a chemical substance asdescribed herein for use as a medicament in the treatment of braindisease associated with cognitive impairment, wherein the brain diseaseto be treated is Alzheimer's disease, the chemical substance is thegluconate salt of GLN 1062, which is administered intranasally, bucallyor sublingually as a 10% weight per volume (w/v) solution at an amountof 50 microliters, preferably in a single intranasal spray event, twicedaily.

In one embodiment the chemical substance of the present invention ischaracterised in that intranasal application is carried out byadministering a therapeutically effective amount of the chemicalsubstance using a suitable metered dose device such as a atomizer,sprayer, pump spray, dropper, squeeze tube, squeeze bottle, pipette,ampule, nasal cannula, metered dose device, nasal spray inhaler, nasalcontinuous positive air pressure device, and/or breath actuatedbi-directional delivery device.

In one embodiment the invention relates to a chemical substance asdescribed herein for use as a medicament in the treatment of braindisease associated with cognitive impairment, wherein the sublingualadministration is carried out by administering a therapeuticallyeffective amount of the chemical substance under the tongue by placingone or more drops of a solution, or an amount of particulate in the formof freeze-dried powder or emulsion underneath the tongue and/or byspraying the underside of the tongue with a preselected volume of aliquid composition comprising the chemical substance.

In one embodiment the invention relates to a chemical substance asdescribed herein for use as a medicament in the treatment of braindisease associated with cognitive impairment, wherein the buccaladministration is carried out by administering a therapeuticallyeffective amount of the chemical substance to the buccal vestibuleinside the mouth between the cheek and the gums as a freeze-dried powderor emulsion, or an orally disintegrating or orodispersible tablet (ODT).

In one embodiment the chemical substance of the present invention ischaracterised in that the subject is a mammal, preferably a human.

In one embodiment the chemical substance of the present invention ischaracterised in that the brain disease to be treated is selected fromAlzheimer's and/or Parkinson's disease, other types of dementia,schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy,oxygen and nutrient deficiencies in the brain after hypoxia, anoxia,asphyxia, cardiac arrest, chronic fatigue syndrome, various types ofpoisoning, anaesthesia, particularly neuroleptic anaesthesia, spinalcord disorders, inflammation, particularly central inflammatorydisorders, postoperative delirium and/or subsyndronal postoperativedelirium, neuropathic pain, abuse of alcohol and drugs, addictivealcohol and nicotine craving, and/or effects of radiotherapy.

In one embodiment the chemical substance of the present invention ischaracterised in that the distribution of the chemical substance in apatient after administration exhibits a brain-to-blood concentrationratio of more than 5, preferably more than 10, more preferably between15 and 25.

The invention further relates to the use of the chemical substance asdescribed herein for the treatment of brain disease associated withcognitive impairment by administering a therapeutically effective amountof said chemical substance by a transmucosal route selected from thegroup consisting of intranasal, buccal and/or sublingual administration.

In another aspect the present invention relates to a pharmaceuticalcomposition comprising the chemical substance according to Formula I, IIor GLN 1062 of the present invention and preferably one or morepharmaceutically acceptable carriers for use in the treatment of braindiseases associated with cognitive impairment in a mammal, characterisedin that the composition is suitable for intranasal, buccal and/orsublingual application. The invention therefore relates to nose drops orunder-the-tongue drops in the form of a liquid composition fortransmucosal administration via nasal or buccal mucous membranes.

The invention relates to a pharmaceutical composition comprising thechemical substance according to Formula I, II or GLN 1062 of the presentinvention for use as a medicament in the treatment of brain diseasesassociated with cognitive impairment via transmucosal administration,wherein the composition is an aqueous solution, comprising 2 to 40%,preferably 5 to 15% and more preferably 10% weight per volume (w/v) ofthe chemical substance.

In one embodiment the invention relates to a pharmaceutical composition,wherein the composition comprises N-ethylpyrrolidone. In a preferredembodiment the invention relates to a pharmaceutical composition,wherein the composition comprises a self-microemulsifying drug delivery(SMEDD) system. Such compositions preferably comprise glycerylcaprylate, polyethyleneglycol, propyleneglycol and/ordiethyleneglycolemonoethylether.

The invention also relates to a pharmaceutical composition comprisingthe chemical substance according to Formula I, II or GLN 1062 of thepresent invention for use as a medicament in the treatment of braindiseases associated with cognitive impairment via transmucosaladministration, wherein the composition comprises a sustained releaseformulation comprising chitosan.

A further embodiment of the invention relates to a pharmaceuticalcomposition comprising a micronized powder formulation of the chemicalsubstance to be administered, preferably with a particle size of 0.01 to1000 microns, preferably 0.1 to 100 or 1 to 10 microns.

The invention relates to a pharmaceutical composition comprising thechemical substance according to Formula I, II or GLN 1062 of the presentinvention for use as a medicament in the treatment of brain diseasesassociated with cognitive impairment via transmucosal administration,wherein the composition comprises a sublingual tablet, preferablycomprising lactose monohydrate, corn starch, polyvinylpyrrolidone (PVP)and/or magnesium stearate, and optionally with a flavouring agent.Alternatively the composition may comprise a sublingual tabletcomprising mannitol, sodium starch glycolate, croscarmellose, ascorbicacid and/or magnesium stearate, optionally with a flavouring agent.

The invention also relates to a pharmaceutical composition comprisingthe chemical substance according to Formula I, II or GLN 1062 of thepresent invention for use as a medicament in the treatment of braindiseases associated with cognitive impairment via transmucosaladministration, wherein the composition comprises a multi-layered tabletwith digestive acid resistant coating, such as comprising eudragit.

In a preferred embodiment the pharmaceutical composition of theinvention comprises the substance to be administered at 2 to 40% weightper weight (w/w), preferably 10 to 30%, or more preferably 5, 10, 20 or30% weight per weight (w/w) in a composition in the form of aself-microemulsifying drug delivery (SMEDD) system, sustained releaseformulation comprising chitosan, micronized powder formulation orsublingual or buccal tablet.

In a particularly preferred embodiment, the CNS therapeutic is theestablished anti-dementive drug galantamine, the pro-drug is the benzoicester of galantamine (galantamine benzoate, GLN 1062, otherwisementioned as “Memogain”), and the salt forms used for intranasaldelivery are preferably the lactate, gluconate, maleate or saccharatesalts of said benzoylester of GLN 1062. GLN 1062 is also known as(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-Benzofuro[3a,3,2-ef][2]benzazepin-6-ol,6-benzoate. For example, the gluconate salt of Memogain is also known asthe galantamine benzoate gluconate.

The invention also relates therefore to a method of treatment for braindisease associated with cognitive impairment by administering atherapeutically effective amount of the above described chemicalsubstances by a transmucosal route selected from the group consisting ofintranasal, buccal and/or sublingual administration. The method oftreatment of the present invention may also be further defined byembodiments of the invention provided herein with respect to theadministration regime, the substance itself and/or other administrationparameters.

DETAILED DESCRIPTION OF THE INVENTION

A detailed description of the present invention encompasses thefollowing developments:

(1) In preferred embodiments pro-drugs of galantamine are provided thatare significantly more lipophilic than their parent compounds, therebyenhancing their passive transport through the blood-brain barrier (BBB)into the brain.

(2) These pro-drugs are pharmacologically inactive and hence do notproduce any significant GI or other side effects, as long as they remainun-cleaved in the particular tissue. After enzymatic cleavage, from eachmolecule of pro-drug one molecule of parent drug is formed, therebyproducing the full pharmacological effect of the drug. If cleavage ispreferentially in the brain, due to enhanced distribution into thisorgan, and the availability of suitable endogenous enzyme(s) therein, asignificantly higher concentration of drug at the target sites in theCNS and consequently larger medically beneficial effects are achieved.

(3) Preferential transport to the target organ brain is furtheroptimized in a surprising and beneficial manner by transmucosal routesof administration in the oral or nasal cavity.

(4) High-dose formulations and extended-release formulations of thepro-drugs further optimize the pharmacokinetics of uptake into the brainand maintain drug levels therein for optimal effectiveness of action.

Taken together, these features of the formulations of pro-drugsdescribed herein, foster delivery to the brain of much higherconcentrations of drug than can be achieved by oral administration inform of tablets of the unmodified drug. The improved distribution of thedrug to the brain dramatically reduces all locally produced side effectsin the GI tract, thereby permitting to immediately apply an efficaciousdose of the drug to its CNS-located target molecules, e.g. nicotinicreceptors and cholinesterases.

As the blood-brain barrier (BBB), located at the level of the braincapillaries, is the major barrier to the passage of drugs from the bloodcompartment to the brain, initial focus on optimizing penetration of thepro-drugs through the BBB yielded promising results. The brainmicrovessel endothelial cells forming the BBB have as typicalmorphological characteristics tight junctions between cells, absence offenestrations and diminished pinocytotic activity. A variety of enzymesfurther contributes to the restrictive nature of the BBB. The ability ofdrugs to cross the BBB mostly depends on their physicochemicalproperties, such as their lipophilicity. Consequently, the compoundsconsidered in the present disclosure all are pro-drugs with improvedlipophilicity, in comparison to their parent compounds.

The BBCR is to be understood as the brain-to-blood concentration ratioafter transport equilibrium via the BBB has been achieved.

In general, a Log P value of a galanthamine derivative of approximately1.3 leads to a BBRC (brain-to-blood concentration ratio) ofapproximately 2 or somewhat less than 2, a log P value of approx. 2leads to a BBRC of approx. 5 to 10 and a log P value of approx. 3 leadsto a BBRC of approx. 20 or over 20. This is intended as a guideline forcomparing log P values with BBB permeability and may vary for someparticular compounds. This guideline does not represent a limitingfeature of the invention.

Pro-drugs are defined as per se therapeutically inactive agents that arepredictably transformed in specific locations in the body to activemetabolites. In this sense, pro-drugs are inactive precursors of parentdrugs that undergo transformation into active agents in vivo byenzymatic cleavage or chemical spontaneous process(es) in a predictablefashion. In the pro-drugs discussed here, there exists preferably acovalent ester linkage between the parent drug and the selectedtransport pro-moiety, and upon cleavage of this ester bond, ideally inthe target organ brain, the inactive pro-drug releases the active parentdrug at or close to its target sites in the CNS.

Rapid absorption in the oral cavity is best achieved by sublingualadministration, as the mucosal thickness in this area is lower than inother buccal areas, in addition to being significantly less keratinized(Shojaei A (1998) Buccal mucosa as a route for systemic drug delivery: areview. J Pharm Pharmaceut Sci 1: 15-30). Fast dissolving sublingualformulations, such as rapidly degrading tablets or liquid-filledcapsules, can additionally help reducing enzymatic degradation ofpro-drug in saliva. The nasal cavity also provides a promising startingpoint for alternative administration regimes, with its large surfacearea, high vasculature and low enzymatic environment. Intranasaldelivery is capable of providing a similarly high level ofbioavailability as intravenous administration with the advantages ofnon-invasiveness, ease of self-administration, patient comfort andpatient compliance in comparison to the latter. These advantages mayhave been known generally by practitioners of the art; however,significant hurdles remain for developing such application routes. Forchronic systemic delivery, the problems of epithelial damage andtoxicity need to be solved, and that for sufficient bioavailability highconcentrations of drug in small volumes of vehicle are provided. Thisrequires first selection of suitable chemical compounds that enable therequired formulations and concentrations, in addition to findingappropriate methods for administration and finally developing preferredsalts and/or solutions thereof that allow optimal administration ofeffective substance to the brain.

It was therefore not predictable in light of the prior art, whichcompounds would provide successful outcomes with regard to alternativeadministration modes. It can also not be predicted from the prior art,which salts and/or formulations could be generated for the prodrugs ofthis invention, nor whether these products would provide an effectiveBBB penetration and cleavage to active substance in the brain.

Suitable pro-drug formulations according to the invention were selectedas follows. By way of monitoring the concentrations of the pro-drug inwhole brain and blood plasma after intravenous injection of the pro-druginto animals, we determined their basic BBCR.

By additionally monitoring the concentrations of the released parentdrug in brain and blood, we determined the rates and effectiveness ofconversion from pro-drug to drug. These studies demonstrated that uptakeof pro-drug into the brain was very fast indeed, and that the fastuptake strongly favored conversion of pro-drug to drug to take place inthe brain. As most of the parent drugs under study are known to act ascholinesterase inhibitors, we reasoned and then proved that the relatedpro-drugs are cleaved to their active parent drugs by esterases of thebutyrylesterase and carboxyesterase type.

We then changed to transmucosal delivery in the oral and nasal cavityand determined in animal models again the kinetics of uptake into thebrain, the drug levels achieved therein, and the pharmacodynamicsachieved in comparison to oral delivery of the derivative and parentdrug. The administration of the chemical substances described herein viatransmucosal routes represents a surprising and unexpected advantage incomparison to previously known methods of oral administration. It wasneither disclosed nor suggested in the prior art that certainderivatives of galantamine could be preferentially transported into thebrain via transmucosal administration. As described above, previousattempts of intranasal application of galantamine had failed due to poorphysicochemical properties. Surprisingly, the transmucosal applicationof the galantamine derivatives as described herein as preferred chemicalsubstances does enable improved brain-to-blood concentration ratios.This effect is surprising in light of the previous failures of similaradministration regimes for galantamine itself.

A goal of the present invention is therefore to present novel CNStherapeutics having optimal brain bioavailability due to beingformulated as lipophilic pro-drugs and administered via transmucosalabsorption pathways in the oral or nasal cavity

The invention is based on the fundamental understanding that the basecompound itself, i.e. galantamine, has to be delivered to the brain bycrossing the blood-brain barrier. Due to the fact that galantamineitself has a very low Log P value and therefore is not able to pass theblood brain barrier in sufficiently effective amounts, it is necessaryto modify the base compound in a manner which makes the substance morelipophilic in order to more efficiently cross the blood-brain barrier.Once the substance has reached the brain, the modified base compound,preferably a chemical substance (CS) according to formula I or II, isreconverted by enzymatic cleavage of the ester bond on the R1 residue tothe effective base compound itself, namely galantamine.

An aim of the invention is to deliver the chemical compound in a wayinto the brain to make sure that an effective amount of the basecompound (after cleavage within the brain following crossing theblood-brain barrier) is available in the brain, in particular in orderto ensure higher bioavailability of the later base compound galantamine.

As previously described (Maelicke et al., Memogain is a galantaminePro-drug having Dramatically Reduced Adverse Effects and EnhancedEfficacy, J Mol Neurosci (2010) 40:135-137) the substance according toformula I is an inactive pro-drug of galantamine having more than10-fold higher bioavailability in the brain than the same doses ofgalantamine Said derivative of galantamine can be obtained by a one-stepchemical modification of the parent drug (galantamine). The modificationalmost completely abolishes the pharmacological activity of galantamineon its two major targets in the human body, nicotinic acetylcholinereceptor (nAChR) and acetylcholinesterase (AChE).

At the physiologically interesting concentration of 1 Memogain has lessthan 4% of the esterase inhibition induced by the same concentration ofgalantamine.

Synthesis, preparation and pharmacokinetic data of the substanceaccording to formula I are previously described in detail in WO2009/127218 A1 as well as in US 2009/0253654 A1, both are herewithincorporated by reference.

It is preferred to administer the chemical substance of the presentinvention by a route selected from the group consisting of intranasal,buccal, including sublingual, and/or intravenous administration. Thisway of administration guarantees a relative short bio-transport from thesite of application, namely mouth, nose, tongue, buccal, intravenous, tothe brain. Therefore the chance of disintegration of the chemicalsubstance is low and the likelihood of effective transport from thenearby place of application to the blood-brain barrier is high.

In a preferred embodiment, the chemical substance is used as a salt,preferably a quaternary ammonium salt, preferably a lactate, gluconate,maleate or saccharate salt, having a solubility in water of at least10%, preferentially of more than 20%.

It is intended to use the chemical substance in manner that enablesdistribution of the chemical substance in a patient after administrationat a brain-to-blood concentration ratio of more than 5, preferably morethan 10, more preferably between 15 and 25.

In a preferred embodiment, the CNS therapeutics are galantamine andstructurally related compounds, the pro-drugs are aliphatic, aromaticand heteroaromatic esters of alcoholic OH-groups being essential for thepharmacological activity of the therapeutics. To be suitable fortransmucosal delivery in the oral or nasal cavity, they are formulatedas high-concentration aqueous salt solutions, or as emulsions, or asselfmicroemulsifying drug delivery systems (SMEDDs) or as micronizedpowder formulations. It was surprising, that the pharmaceuticallyapplicable solutions of Memogain salts fulfilled the criteria forappropriate stability, concentration, pH, osmolarity, small and nasalmucosal tolerance in solution for intranasal application, as describedin the following table 1.

TABLE 1 Acceptance criteria Preclinic Phase 1 Market Desired maximal 25%25% 10% concentration Acceptable maximal 20% 10% 5% concentration pH4.5-7 5-6.5 5-6.5 Chemical stability >3 hours >7 days >2 years Stabilityof solution >3 hours >7 days >2 years % F in rat >80% n.a. n.a.Osmolarity >250 mosmol/1 >250 mosmol/1 >250 mosmol/1 Smell notunpleasant not unpleasant not unpleasant Tolerance of nasal nosignificant no irritation in no irritation in mucosa irritation humanhuman over during 28-day period of repeat dose administration study inrat & dog

The pharmaceutical composition is preferably an aqueous solution,comprising 2 to 20% weight per volume (w/v), preferably 5 to 15% weightper volume (w/v), more preferably 10% weight per volume (w/v) of thechemical substance. To be suitable for transmucosal delivery in the oralor nasal cavity, they are formulated as high-concentration aqueous saltsolutions, or as emulsions, or as selfmicroemulsifying drug deliverysystems (SMEDDs) or as micronized powder formulations.

The term transmucosal administration relates to the entering of apharmaceutical agent through, or across, a mucous membrane. Thetransmucosal routes of administration of the present invention aredefined as intranasal, buccal and/or sublingual.

Nasal or intranasal administration relates to any form of application ofthe prodrug or pharmaceutical composition thereof to the nasal cavity.The nasal cavity is covered by a thin mucosa which is well vascularised.Therefore, a drug molecule can be transferred quickly across the singleepithelial cell layer without first-pass hepatic and intestinalmetabolism. Intranasal administration is therefore used as analternative to oral administration of for example tablets and capsules,which lead to extensive degradation in the gut and/or liver.

Buccal administration relates to any form of application that leads toabsorption across the buccal mucosa, preferably pertaining to adsorptionat the inside of the cheek, the surface of a tooth, or the gum besidethe cheek.

Sublingual administration refers to administration under the tongue,whereby the chemical comes in contact with the mucous membrane beneaththe tongue and diffuses through it.

Pharmaceutical compositions suitable for buccal and/or sub-lingualadministration may comprise additional pharmaceutically acceptablecarriers, for example a buccal dosage unit may comprise the active agentto be administered in addition to a polymeric carrier that bioerodes andprovides for delivery of the active agent over a predetermined timeperiod, and, preferably, a lubricant, such as magnesium stearate.Additional carrier agents are known to one in the art. This active agentcan be physically compounded with materials of some or all of classes ofingredients that function as pH controls, preservative agents, viscositycontrol agents, absorption enhancers, stabilizing agents, solvents, andcarrier vehicles. Such agents may be present in either solid or liquidforms of the pharmaceutical composition.

A self-microemulsifying drug delivery system (SMEDDS) may be present insaid pharmaceutical composition, meaning a drug delivery system thatuses a microemulsion achieved by chemical rather than mechanical means.That is, by an intrinsic property of the drug formulation, rather thanby special mixing and handling. It employs the familiar effect displayedby anethole in many anise-flavored liquors. Microemulsions havesignificant potential for use in drug delivery, and SMEDDS (includingso-called “U-type” microemulsions) are the best of these systemsidentified to date. SMEDDS are of particular value in increasing theabsorption of lipophilic drugs taken by mouth. SMEDDS in may include ina non-limiting manner include formulations of the drugs anetholetrithione, oridonin, curcumin, vinpocetine, tacrolimus, berberinehydrochloride, nobiletin and/or piroxicam.

The salt relates to any salt of the compounds of formulae I-II or of GLN1062 itself. The term salt preferably refers to compounds comprising aprotonated, positively charged N atom in the 7-member ring structure ofthe base compound.

“Administration” or “treatment,” as it applies to an animal, human,experimental subject, cell, tissue, organ, or biological fluid, refersto contact of a pharmaceutical, therapeutic, diagnostic agent, compound,or composition to the animal, human, subject, cell, tissue, organ, orbiological fluid. “Administration” and “treatment” can refer, e.g., totherapeutic, placebo, pharmacokinetic, diagnostic, research, andexperimental methods. “Treatment,” as it applies to a human, veterinary,or research subject, refers to therapeutic treatment, prophylactic orpreventative measures, to research and diagnostic applications.

The invention encompasses administration of an effective amount ofchemical substance as described herein to a patient in need thereof.“Effective amount” or “therapeutically effective amount” means an amountsufficient to ameliorate a symptom or sign of a disorder orphysiological condition or an amount sufficient to permit or facilitatea diagnosis of the disorder or physiological condition. An effectiveamount for a particular patient or veterinary subject may vary dependingon factors such as the condition being treated, the overall health ofthe patient, the method route and dose of administration and theseverity of side effects. An effective amount can be the maximal dose ordosing protocol that avoids significant side effects or toxic effects.The effect will result in an improvement of a diagnostic measure,parameter, or detectable signal by at least 5%, usually by at least 10%,more usually at least 20%, most usually at least 30%, preferably atleast 40%, more preferably at least 50%, most preferably at least 60%,ideally at least 70%, more ideally at least 80%, and most ideally atleast 90%, where 100% is defined as the diagnostic parameter shown by anormal subject. “Effective amount” also relates to an amount of theprodrug substance or pharmaceutical composition thereof, sufficient toallow or facilitate the amelioration and/or diagnosis of a symptom orsign of a disorder, condition, or pathological state.

Preferred chemical substances according to the present invention areprovided in Table 2.

TABLE 2 molregno molstructure abbrev. GLN-1062

Bz-Gal GLN-1081

4-Cl-Bz-Gal GLN-1082

4-MeO-Bz-Gal GLN-1083

4-Me-Bz-Gal GLN-1084

3,4-Cl2-Bz-Gal GLN-1085

4-tBu-Bz-Gal GLN-1086

3-CF3-4-Cl-Bz-Gal GLN-1088

4-CF3-Bz-Gal GLN-1089

2,4-Cl2-Bz-Gal GLN-1090

4-NO2-Bz-Gal GLN-1091

3-Cl-Bz-Gal GLN-1092

3-CF3-Bz-Gal GLN-1093

3-NO2-Bz-Gal GLN-1094

3,5-Cl2-Bz-Gal GLN-1095

3-Me2N-Bz-Gal GLN-1096

3-Me-Bz-Gal GLN-1097

2-Cl-Bz-Gal GLN-1098

2,4-F2-Bz-Gal GLN-1099

2,5-Cl2-Bz-Gal GLN-1100

4-F-Bz-Gal GLN-1101

4-NMe2-Bz-Gal GLN-1102

4-NH2-Bz-Gal GLN-1103

3-Me-4-NMe2-Bz-Gal GLN-1104

3,4-OCH2O-Bz-Gal GLN-1105

4-Ac-Bz-Gal GLN-1113

2-AcO-Bz-Gal GLN-0993

n-Hex-Gal GLN-1060

GLN-1061

GLN-1106

3-Th-Bz-Gal GLN-1107

2-Th-Bz-Gal GLN-1108

5-Cl-2-Th-Bz-Gal GLN-1109

5-Im-Bz-Gal GLN-1110

5-OA-Bz-Gal GLN-1111

5-Th-Bz-Gal GLN-0926

Nic-Gal

FIGURES

The invention is further described by the figures. These are notintended to limit the scope of the invention.

FIG. 1: Powder diffraction diagram of Memogain gluconate obtained usingdioxane.

FIG. 2: Adsorption/desorption isotherm of Memogain gluconatemonohydrate.

FIG. 3: Weight loss on heating of Memogain gluconate monohydrate.

FIG. 4: Differential scanning calorimetry (DSC) the wet cake of Memogaingluconate.

FIG. 5: Powder diffraction diagram of Memogain gluconate obtained usingethanol.

FIG. 6: Experimental brain-to-blood concentration ratios for galantamineand several pro-galantamines.

FIG. 7: Intranasal Memogain is more potent than galantamine Mice werechallenged with scopolamine and dosed with increasing concentrations oforal galantamine and intranasal Memogain before performance evaluationin the mouse T-maze model.

FIG. 8: The first-pass effect of Gln-1062 was evaluated afterintravenous and intraportal dosing of 3 mg/kg in Wistar rats.

FIG. 9: Intranasal administration of Memogain leads to low amounts ofliberated galantamine in plasma.

FIG. 10: Memogain produces fewer gastro-intestinal side effects thangalantamine.

FIG. 11: Lower toxicity of Memogain is due to the lower steady-stateplasma levels of galantamine resulting from enzymatic cleavage of thepro-drug.

FIG. 12: The pharmacokinetic profiles of Memogain and galantamine infemale Wistar rat after intra-nasal application of 5% Memogain salt in10% NEP in water, 10 μL per nostril, a total of 20 μL containing 1 mgare shown below.

FIG. 13: Mice were injected with 3 mg/kg i.v. of either Memogain orgalantamine. The data demonstrate that galantamine does not penetratethe brain well compared to Memogain.

FIG. 14: Intranasal administration of Memogain in a Rat PK study. 5mg/kg intranasal (i.n.) Memogain dosing was performed under GLP-likeconditions.

EXAMPLES

The invention is further described by the following examples. Theexamples are intended to further describe the invention by way ofpractical example and do not represent a limiting description of theinvention.

Example 1. High-Concentration Aqueous Salt Solutions and Organic SolventSolutions of Pro-Drugs

For one of the drugs considered herein, galantamine, intranasalformulations were previously developed on the basis of aqueous solutionsof highly soluble salts (WO 2005/102275 A1; Leonhard A K et al. (2005)Development of a novel high-concentration galantamine formulationsutable for intranasal delivery. J Pharmaceut Sciences 94: 1736-1746;Leonard A K et al. (2007) In vitro formulation optimization ofintranasal galantamine leading to enhanced bioavailability and reducedemetic response in vivo. Int J

Pharmaceutics 335: 138-146).

While the reported galantamine salt formulations allowed administrationof galantamine at similarly high doses as is recommended for oraladministration of tablets, intranasal administration did not improve thebrain/blood concentration ratio of galantamine, as the physicochemicalproperties of the drug and hence penetration through the BBB did notchange by this approach. In contrast, when the same salt formulationsare formed from the pro-drugs disclosed herein, a large increase inlipophilicity (log P) is achieved, concomitantly with much betterpenetration through the BBB. This can be seen in FIG. 1.

The combination of salt formation with prodrug properties, inparticularly with regard to GLN 1062, shows a synergistic effect ofimproved absorption through the mucosal membrane and direct uptake tothe brain, thereby enabling enhanced delivery to the site of action.

The blood-brain barrier penetration achieved by the various salts of theinvention—in comparison to both the galantamine base compound, but alsoin comparison to oral administration of the derivatives themselves, —isincreased in an unexpected and significant manner.

1.1. Salt of Memogain with Acetic Acid: (General Procedure A):

To the solution of Memogain (502 mg, 1.28 mmol in 2 ml 96% ethanol)acetic acid (463 mg, 7.71 mmol) was added and the resultant solution wasstirred for some time and left overnight for salt formation resulting inthe precipitation of the acetate salt. The yield was improved byaddition of diethyl ether and the precipitate was filtered and washedwith 96% ethanol. The precipitate was dried in a desiccator at r.t. at40 mbar for 20 h. Results: colorless solid (Hygroscopic). Yield: 62%,m.p.: 89.3-91.2° C., HPLC>95%. Elemental analysis: Calcd. forC₂₄H₂₅NO₄*1.5 CH₃COOH C:71.24, H: 6.46, N: 3.32 Found C: 71.36, H: 6.17,N: 3.43.

Several other crystal forms containing 1-2 molar equivalents of aceticacid were obtained in a similar manner by changing the relative amountsof Memogain and acid as well as the precipitation method.

1.2. Salt of Memogain with Lactic Acid: (General Procedure B):

To the solution of 2.5 g Memogain (6.4 mmol) in methanol (4 ml) asolution of 95% racemic lactic acid (7.85 mmol) in methanol (2 ml) wasadded at 40-50° C. and stirred for 20 min. The solvent was evaporatedand the resulting residue was dried first using a rotavap for 2 hrs at 9mbar and at 50−60° C. followed by overnight drying at 40 mbar at r.t.resulting in a solid light yellow foam that was highly hygroscopic.Yield: 98.92%, m.p.: 62.9-64.1° C., Elemental analysis: Calcd. forC₂₄H₂₅NO₄*1.1 C₃H₆O₃ C: 66.84, H: 6.49, N: 2.86. Found: C: 66.69, H:6.45, N: 2.80 HPLC purity>97%.

In a similar manner the corresponding salt with (+)-lactic acid wasobtained: Calcd. for C₂₄H₂₅NO₄*1.5 C₃H₆O₃ C: 65.01, H: 6.51, N: 2.66.Found: C: 64.91, H: 6.28, N: 2.70.

1.3. Salt of Memogain with Citric Acid:

Using general procedure B but dry ethanol as solvent the citrate wasobtained in 91.0% yield as sticky solid that turned into a colorlesssolid after trituration using dry diethyl ether followed by high vacuumevaporation with m.p.: 117.5-119° C. Elemental analysis: Calcd for C:73.64, H: 6.44, N: 3.58 Found C: 59.61, H: 5.93, N:2.26. HPLC>97%

1.4. Salt of Memogain with Saccharic Acid (General Procedure C):

To a solution of Memogain (1120 mg) in 96% ethanol (4 ml) was added asolution of saccharolactone (200-604 mg) in 96% ethanol (3 ml) at 60°.The hot solution was immediately diluted with ethyl acetate resulting inthe formation of a colorless precipitate that was filtered after coolingto 5° for 2 hrs, washed with ethyl acetate and dried at 40 mbar for 20hrs at r.t. to give a 83.7% yield of the saccharic acid salt ascolorless solid with m.p.: 132-134° C. and HPLC-purity of >97%.Elemental analysis: Calcd. for C₂₄H₂₅NO₄*C₆H₁₀O₈ C: 59.89, H: 5.86, N:2.33. Found: C: 60.10, H: 5.61, N: 2.37. The lactone of saccharic acidis hydrolyzed with water present under these conditions resulting in thesalt described.

1.5. Salt of Memogain with Gluconic Acid:

Following in general procedure C starting from Memogain (150 mg, 0.38mmol) but using dioxane as solvent and a solution of D-gluconic aciddelta-lactone (68.2 mg, 0.38 mmol) in dioxane containing water (13 mg,0.76 mmol) and stirring at 50-60° C. for 30 min. until a clear solutionwas obtained followed by addition of dry diethyl ether (10 ml) to thecooled solution resulted in a colorless precipitate that was filtered,washed with diethyl ether and dried to obtain 170 mg (75.6%) of the saltas colorless, crystalline solid. m.p.:159.3-159.4° C. HPLC purity>98%Elemental analysis: Calcd. for C₂₄H₂₅NO₄*1.5 C₆H₁₂O₇ C: 57.80, H: 6.32,N: 2.04. Found: C: 58.22, H: 5.98, N: 2.28. The powder diffractiondiagram of this salt is shown in FIG. 1.

From a similar experiment on twice the scale but without adding diethylether for precipitation spontaneous crystals were formed on standing atr.t. for 3 days that were filtered, washed with dioxane and dried toobtain 145 mg (32%) of the 1:1 salt as colorless crystals with m.p.173.3-173.4° C. Calcd. for C₂₄H₂₅NO₄*C₆H₁₂O₇ C: 61.32, H: 6.35, N: 2.38.Found: C: 61.65, H: 6.27, N: 2.64. Microtitration of this salt verifiedthe stochiometry calculated from the elemental analysis.

Under similar conditions but prolonged drying other salt-formscontaining 0-2 equival. of water in the crystal were obtained. It isknown that D-gluconic acid delta-lactone is hydrolyzed to gluconic acidby water.

In an alternative procedure ethanol was used as a solvent. Thus Memogain(9.4 g, 24 mmol) in 96% ethanol) was added to a solution of D-gluconicacid delta-lactone (6416 mg, 36 mmol) in 96% ethanol (10 ml) and heatedto 50-60° C. for 30 min. until a clear solution was obtained that waskept at r.t. for 2 days with the formation of a colorless precipitatethat was filtered, washed with dry ethanol (2×20 ml) and isopropanol (60lm) and dried at 40 mbar at r.t. for 20 hr to obtain 7.91 g (84.2%) ofthe product as colorless crystalline solid m.p.: 122-126° C., HPLCpurity>98%. Elemental analysis: Calcd. for C₂₄H₂₅NO₄*C₆H₁₂O₇*H₂O C:59.50, H: 6.49, N: 2.31. Found: C: 59.60, H: 6.59, N: 2.32.

This salt was used to obtain the adsorption/desorption isotherm of water(FIG. 2) as well as the weight loss on heating (FIG. 3). Furthermore bydifferential scanning calorimetry (DSC) of the wet cake of Memogaingluconate it was determined, that drying takes place between 53 and 87°C. and melting around 123° C. (FIG. 4). The powder diffraction diagramof this salt is shown in FIG. 5

^(1H)NMR (200 MHz, D2O): δ 7.35-7.46 (d, 2H), 7.09-6.94 (t, 1H),6.92-6.80 (t, 2H), 6.59-6.36 (m, 2H), 6.14-6.00 (d, 1H), 5.85-5.72 (m,1H), 5.16-5.07 (s, 1H), 4.48-4.31 (m, 4H), 4.13-3.84 (m, 5H), 3.73-3.53(m, 6H), 3.53-3.39 (m, 5H), 2.76-2.58 (s, 3H) 2.39-2.21 (d, 1H),2.06-1.69 (m, 3H)

^(13C)NMR (50 MHz, D2O): δ 178.39 (s, 1C), 167.03 (s, 1C), 146.09 (s,1C), 145.11 (s, 1C), 133.09 (s, 1C), 131.57 (s, 1C), 129.26 (s, 1C),128.04 (s, 1C), 123.75 (s, 1C), 123.40 (s, 1C), 119.02 (s, 1C), 118.74(s, 1C) 118.67 (s, 1C), 112.05 (s, 1C), 85.82 (s, 1C), 73.93 (s, 1C),73.52 (s, 1C), 72.46 (s, 1C), 71.07 (s, 1C), 70.81 (s, 1C), 64.23 (s,1C), 62.54 (s, 1C), 58.51 (s, 1C), 55.52 (s, 1C), 53.98 (s, 1C), 46.50(s, 1C), 40.96 (s, 1C) 40.82 (s, 1C), 32.07 (s, 1C), 26.83 (s, 1C).

Using the general procedures A, B and C the following salts wereprepared on a 0.5 to 10 mmol scale in a similar manner and un-optimizedyields of 42-91% were obtained. For those salts that were obtained in acrystalline state the melting points are indicated. Salts that showedsolubility in water higher than 10% or even 20% were investigatedfurther.

In addition to this list, pharmaceutically acceptable salts as describedin table 1 of the book Pharmaceutical Salts, Properties, Selection andUses, Stahl, P. H. and Wermuth, C. G., eds., VHCA Verlag 2002, can beused.

1.6. Solubility Test

10 mg of the corresponding salt and 100 microliters of water weresonicated for 5 min at r.t. The resulting solution or suspension wascentrifuged for 3 min. and filtered using a filter tip. 10 microlitersof the filtrate was transferred in a volumetric flask and diluted to10.0 ml with water to obtain the sample solution. 20 microliters of thissample solution was injected for HPLC and the amount of Memogainquantified using a Merck Chromolith RP18 column and a gradient of 5% to60% acetonitrile and water, both solvents containing 0.1% formic acid,injection volume: 20 microliters.

The Memogain salts of acetic acid, maleic acid, lactic acid (lactatesalt), citric acid, saccharic acid (saccharate salt) and gluconic acid(gluconate salt) all showed solubility at above 10% in water.

The lactate, gluconate, maleate and saccharate salts of Memogain showedsolubility above 10% weight per volume (w/v), sometimes formingmeta-stable salts at 20% concentration in solution. The gluconate saltshowed solubility at 40% weight per volume (w/v) and the saccharate saltat 70% weight per volume (w/v).

TABLE 3 Additional Memogain Salts Acid m.p.(° C.) Ascorbic acid 110-131(decomp.) Arabic acid 213 (decomp.) Adipic acid DL-Mandelic acidD-Glucoheptono-1,4-lactone 147 (decomp.) Formic acid 146-147 Fumaricacid Galactaric acid 143-144 D-(+)-Galacturonic acid 148-151 Glucuronicacid 145-146 Glycolic acid  97-103 Hydrobromic acid 221-222 Hydroxycitric acid Hydrochloric acid Isethionic acid 191-195 Maleic acidL-(−)-Malic acid 107-108 Malonic acid Nicotinic acid 117-118 Phosphoricacid Succinic acid Sulfuric acid 172-173 L-(+)-Tartaric acid 185-186D-(−)tartaric acid 212-213 Meso tartaric acid 107-109

Particularly preferred are quaternary nitrogen salts (otherwise termedquaternary ammonium salts) of acetic acid, maleic acid, lactic acid(lactate salt), citric acid, saccharic acid (saccharate salt) andgluconic acid (gluconate salt).

These acids form salts with Memogain and other galantamine pro-drugnitrogen bases having solubility of up to 70% at neutral pH in water.While high-concentration of the gluconate salt in aqueous solution ismetastable and is later converted to less soluble stable salt forms, thefully dissolved homogenous solutions can be recovered by warming theaqueous mixtures to >50° C. until precipitations have disappeared. Thesemetastable homogenous solutions remain stable for hours and days,provided that precautions are taken to reduce or avoid precipitationseeding. Appropriate documentation of the dissolution procedure to formsuch metastable (hypercritical) solutions renders these solutionssuitable drug product formulations for use by patients and medicalpersonal. A short warming, for example for 5 minutes by hand, beforeadministration allows optimal administration of such metastablesolutions.

As sustained release aqueous formulations of the pro-drugs discussedhere, we have dissolved in water a powder of the natural biopolymerchitosan, and mixed it with Memogain base or hydrogen salt so as toachieve formulations for intranasal delivery of 5% (w/v) or more (IlliumL et al. (2002). Intranasal delivery of morphine. J Pharmacol Exp Therap301: 391-400). The method of application described in Illium et al isalso suitable for use with the chemical substances of the presentinvention.

Sustained release formulations of Memogain salts comprising chitosanalso proved effective when applied in solid form in oral sublingual orbuccal administration, and showed unexpectedly fast initial absorptionwith long release times.

The preferred salts of the present invention represent preferredembodiments that exhibit unexpectedly surprising and advantageouseffects in comparison to what was disclosed in the prior art or whatcould have been expected by a skilled person in light of the prior art.

The solubility of the particular preferred salts is unexpectedly good,allowing a higher concentration of medicament in the pharmaceuticalcomposition (i.e. in the form of a solution in a particularly preferredembodiment for intranasal administration, but also buccal or sub-lingualapplication). This is of great importance in light of the requirementsmentioned above for compounds that are suitable for intranasal,sublingual or buccal administration. Due to the limited size of thenasal cavity the required concentration of the active substance insolution is high. This means that salts needed to be found, which couldbe very soluble and therefore provided at a high concentration. This issurprisingly the case for the salts mentioned herein, preferably foracetic acid (acetate salt), lactic acid (lactate salt), citric acid,saccharic acid (saccharate salt) and gluconic acid (gluconate salt).

Example 2. Emulsions and Selfmicroemulsifying Drug Delivery Systems(SMEDDs)

Emulsions and SMEDDs are established means of brain delivery systems(Botner S, Sintov A C (2011) Intranasal delivery of two benzodiazepines,Midazolam and Diazepam, by a microemulsion system. Pharmacol Pharmacie2:180-188). In the present application they were produced by mixing thepro-drug under investigation, as nitrogen base or as hydrogen salt, withvarious organic solvents or by mixing with suitable surfactants, oilsand co-surfactants (all recognized as safe; GRAS) under stirring and/orultrasound until a clear solution was achieved. In particular, weavoided using alcohols or other irritant chemicals in the formulationsso as to avoid any irritability of the nasal or buccal mucosa. Typicalcomponents of such microemulsions were Labrasol, N-ethyl-2-pyrrolidone(NEP), glyceryl oleate, PEG, propylene glycol, Transcutol, and suitableoils, such as palmitate. We achieved drug solubilities of the order of10% (w/w), or more, with a maximal water solubilization capacity ofapprox. 50% (the lower the water content, the higher oil concentrationscould be achieved, and the higher the solubility of nitrogen base). Thehighest solubilities of pro-drug nitrogen bases or salts were obtainedat water concentrations around 20% in the microemulsions.

Preferred embodiments of the self-microemulsifying drug delivery (SMEDD)formulation, preferably for Memogain maleate, relate to the following:Used Materials:

Memogain maleate (No. 022563-A-1-1, GALANTOS Pharma GmbH, Germany)

Capmul MCM (Lot: 080726-7, BERENTZ-ABITEC CORP., USA) (glycerylcaprylate/caprate; Pharm. Eur.)

PEG 300/400 (Lot: 1349048-41108320, FLUKA, Vienna, Austria)(polyethyleneglycol; Pharm. Eur.)

Propyleneglycol (Lot: S44324-108, SIGMA, Vienna, Austria)(propyleneglycol; Pharm. Eur)

Transcutol (Lot: 18703CE, SIGMA, Vienna, Austria)(diethyleneglycolemonoethylether; Pharm. Eur.)

Preparation of a 10% Memogain Maleate SMEDD Formulation (1 L):

As the first step, 100 g of Memogain maleate are weighted into anappropriate steel tank.

In the following the solubilizers and fatty oils are added one aftereach other:

170 ml of Capmul MCM

500 ml PEG 300

220 ml Propyleneglycol

110 ml Transcutol

Finally the SMEDD formulation is treated with ultrasound until themixture becomes a clear solution.

The Memogain base and salt emulsion and SMEDD formulations demonstratereduced local irritation of the mucosal surface upon application.Furthermore, the bitter taste of the prodrug is effectively maskedthrough the various lipid and PEG components and no analgesic effect onthe transmucosal surface was evident.

Example 3. Micronized Powder Formulations and Nano-Suspensions ofPro-Drug Crystals

Other suitable formulations for transmucosal delivery are pro-drugnano-crystals and polymeric micro-particles to which pro-drugs areadsorbed. In both cases, the more lipophilic pro-drug bases were used.The formulations were obtained by co-precipitation of polymer andpro-drug, by pearl milling and homogenization in water, or asnano-suspensions of pro-drugs that are lipid conjugates. Such methodsare known to one skilled in the art and could be applied with thechemical substances and methods of administration of the presentinvention.

The micronized powder compositions of GLN 1062 or salts thereof enablefast absorption and a reduction in the bitter taste of the compound,compared to when applied as an aqueous solution.

Example 4. Memogain-Formulations

Solubility of Memogain

Free Base in Water: 26 pg/ml (66 μM)

Maleate in Water: 7.5 mg/ml (15 mM)

Maleate in 0.9% NaCl: 0.6 mg/ml (1.5 mM)

Free Base in Cyclodextrin-Vehicle¹⁾: 8.9 mg/ml (23 mM) ¹⁾ 15% (109 mM)Hydroxypropyl-β-cyclodextrin, 96 mM NaCl

Maleate in Cyclodextrin-Vehicle¹⁾: 21 mg/ml (41 mM)

TABLE 4 Formulations Name GEA1 Type Sublingual Tablet API Memogainmaleate API/Tablet  1 mg Tablet mass 20 mg Carrier Lactose monohydrateEthanol ¹⁾ Corn starch Povidon K30 (polyvinylpyrrolidone (PVP))Magnesium stearate Name GEA2 Type Sublingual Tablet API Memogain maleateAPI/Tablet  2 mg Tablet mass 50 mg Carrier Mannitol Explotab (sodiumstarch glycolate) Croscarmellose Ascorbic acid Magnesium stearate Orangeflavour Name Evonik 1 Type Multi-layered Pellets (ca. 1 mm) withdigestive acid resistant coating API Memogain maleate API-amount 1%Pellet core Cellet 700 (MCC) API-layer Memogain maleate and Methocel E5(HPMC) Subcoating Methocel E5 (HPMC) Coating Eudragit FS30D, Talc,Triethylcitrate Layer thickness Approx. 30 μm bei 15% Coating; Eudragit:also Pellets with 5% and 10 were manufactured. Name Evonik 2 TypeMulti-layered Tablets (appr. 9 mg) with digestive acid resistant coatingAPI Memogain maleate API-amount 2 mg Pellet core Memogain maleat, AvicelPH 102 (MCC), corn starch, Methocel E5 (HPMC), Magnesium stearateSubcoating Methocel E5 (HPMC) Coating Eudragit FS30D, Talc,Triethylcitrate Layer thickness appr. 90 μm bei 15% coating; Eudragit:also Pellets with 5% and 10% were manufactured. ¹⁾ removed duringproduction

The sub-lingual tablets and multi-layered formulations of the presentinvention show surprisingly good adsorption properties, enabling quickuptake and reduced flavour bitterness, in addition to reduced analgesiceffects in the mouth of the patient. The fast adsorption of chemicalsubstance enables a reduced risk of swallowing; thereby ensuring theadministration occurs transmucosally through the oral mucous membrane,avoiding unwanted degradation of the prodrug.

Example 5. Interaction with Carrier Substance and Eudragit(Poly(Meth)Acrylate)

Experiment 1: a small amount (0.1 mg) of Memogain maleate in 1 mlHBSS-Puffer, pH 7.4 was incubated with various carriers at 37° C. 2.5 h.The amount of free (not bound to the particle of the carrier substance)of Memogain was then measured by HPLC. Typical amounts of carriersubstance were applied and shown in Table 5.

TABLE 5 Non-absorbed Memogain Nr. Substance mg carrier (% of control)control none 0 100 1 Lactose 10 105 2 MCC 10 100 3 HPMC 1 105 4 Cornstarch 5 100 5 Eudragit L100 2 21 6 Eudragit FS30D 1.8 7 7 Talc 2 94 8Mg Stearate 0.1 101 9 Mg Stearate + Tw20 0.1 plus 0.1% 103 Tw20 10Aerosil (SiO₂) 1 89 11 Emcompress 10 101 (CaHPO₄) 12 Explotab 2 99 13Triethylcitrat 0.2 101

Result: Eudragit L100 and Eudragit FS30D adsorb Memogain.

Experiment 2: a fixed amount of Eudragit (0.5 mg/ml) was incubated withvarious amounts of Memogainmaleate for 2 h in a saline solution (HBSS).The amount of free (not bound to the particle of the carrier substance)of Memogain was then measured by HPLC. In parallel the solubility of theEudragit amount alone in the salt solution was analysed.

Result: L100 is completely soluble in the provided concentration, FS30Dforms a cloudly solution. FS30D binds to Memogain over the entire testedconcentration range. As of 0.25 mg/ml Memogain forms a precipitate withL100, which can be re-solubilised by the addition of 6% Cycldodextrin(HPCD).

Example 6. In Vitro Studies of Permeation Behavior, Pre-SystemicMetabolism and Stability

Permeation behavior of pro-drug formulations was tested using tissuesamples of 3-4 cm² freshly excised porcine nasal or buccal mucosainserted in an Ussing-type chamber displaying a permeation area of 0.64cm² and a volume of 1 ml on both sides. The apical side of the tissuewas facing the donor compartment. One ml of pre-warmed (37° C.)permeation medium was added to the donor and acceptor chamber. Thetemperature within the chambers was maintained at 37° C. throughout theentire experiment. After a pre-incubation time of 15 min the permeationmedium in the donor chamber was substituted by a 1% solution of thepro-drug formulation under investigation. Every 30 min aliquots of 100μl were withdrawn from the acceptor compartment and immediately replacedby 100 μl of fresh pre-warmed permeation medium over a time period of180 min. The concentration of compounds in the collected aliquots wasdetermined via HPLC. Corrections were made for previously removedsamples. Apparent permeability coefficients (Papp) were calculated.Control samples were withdrawn from the donor compartment after 180 minand analyzed to investigate the stability of the compound in theformulation under investigation.

During the above described permeation experiments, 10 μl aliquots werewithdrawn from the donor compartment at time points 0, 60, 120 and 180min. These aliquots were analyzed by HPLC to determine the degree ofpre-systemic metabolism over time.

Using these methods, aqueous solutions of pro-drug salts, and solutionsof pro-drug bases in organic solvents, co-solvents and surfactants weretested as to their solubility, their permeation coefficient, and theirpre-systemic metabolism and stability. The formulations further studiedhad solubilities of at least 10% (m/v), and permeation coefficients ofpro-drugs of Papp>1.10-6 cm/s. Within the time periods tested, there wasno significant pre-systemic metabolism of pro-drugs in both porcinemucosa preparations.

Example 7. Pharmacokinetics

The pharmacokinetics of pro-drugs and parent drugs after transmucosaldelivery in the nasal or buccal cavity were tested in Wistar rats. Thesedata confirmed rapid (within minutes) uptake into blood and brain of thepro-drugs under investigation, bioavailabilites in the brain ofpro-drugs similar to those produced by intravenous injections, and muchhigher BBRC, as compared to oral delivery as tablet of the relatedparent drug.

Because redistribution of parent drug via BBB to the circulation, afterenzymatic production from pro-drug in the brain, is very fast indeed,pharmacokinetic studies do not suffice to exactly determine themomentary concentrations of parent drug in the brain. We therefore usedpharmacodynamics studies to determine the effective concentrations ofparent drug in suitable experimental conditions, such as the reversal ofscopolamine-induced temporary amnesia in the T-maze cognitive paradigmstudied in mice. These studies confirmed that several fold higher (up to20 fold) BBRC of parent drug (and related effectiveness in cognitiveenhancement) can be achieved by transmucosal delivery of pro-drugformulations via the nasal or buccal cavity.

Experiments directly comparing potency and reduced GI side effects ofMemogain between oral and transmucosal (nasal) administration alsodemonstrate that intranasally administered Memogain exhibitssurprisingly beneficial properties in comparison to orally administeredMemogain.

Pharmacokinetc studies were carried out using intranasal and sublingualadministration of the Memogain maleate salt.

Intranasal Report:

This experimental plan describes the blood and brain pharmacokineticprofiles of the pro-galantamine Memogain maleate and galantamine infemale wistar rat following intra-nasal application of the Memogainmaleate and galantamine Hydrobromide in various formulations.

-   -   a. 5% galantamine in water, 10 μL per nostril, a total of 20 μL        containing 1 mg 5%    -   b. Memogain salt in 10% NEP in water, 10 μL per nostril, a total        of 20 μL containing 1 mg    -   c. 5% Memogain salt in an emulsion, 10 μL per nostril, a total        of 20 μL containing 1 mg    -   d. 20% Memogain salt in an emulsion, 10 μL per nostril, a total        of 20 μL containing 4 mg        -   e. Intravenous administration of Memogain salt at dose rate            of 5 mg\kg (previously carried out as control)

Sublingual Report:

This experimental plan describes the blood and brain pharmacokineticprofiles of the pro-galantamine Memogain maleate and galantamine infemale wistar rat following sub-lingual application of the Memogainmaleate and galantamine Hydrobromide in various formulations.

-   -   a. 5% galantamine in water, 20 μL under tongue containing 1 mg    -   b. 5% Memogain salt in 10% NEP in water, 20 μL under tongue        containing 1 mg    -   c. 5% Memogain salt in an emulsion, 20 μL under tongue        containing 1 mg    -   d. 20% Memogain salt in an emulsion, 20 μL under tongue        containing 4 mg    -   e. intravenous administration of Memogain salt at dose rate of 5        mg\/g as control

Both the intranasal and sublingual studies show that beneficialpharmacokinetic (PK) properties were observed with the maleate salt.Similar results are to be expected from the other preferred salts of theinvention, when considering the additional experimentation describedherein and in light of preliminary studies with nasal or buccal mucosa,which show good uptake across the mucosal membranes of all preferredsalts of the invention. The PK data show that Memogain was detected inthe brain for extended periods of time, and showed high brain to bloodconcentration ratios, indicating that very little of the applied prodrugis carried into the blood stream and subsequently degraded. Over timethe levels of Memogain in the brain decrease, as levels of galantaminein the brain increase, which indicates cleavage of the prodrug to itsactive form in the brain of the subject. One example is shown for theintranasal experiment in FIG. 12, sample b.

The administration of the Memogain salt intranasally provides a veryeffective method of directing the prodrug specifically to the brain,where it is processed thereby releasing the active compound galantamine.

Memogain Gluconate:

Further tests were performed with Memogain gluconate. It has a muchlarger BBRC than galantamine (see FIG. 6). The pharmacokinetics andbrain-to-blood concentration ratios (BBRC) of several galantaminederivatives and their cleavage product galantamine were evaluated afterintranasal administration in Swiss albino mice at a dose of 3 mg/kg.After extraction from brain and blood, the drug concentrations weredetermined by LC/MS/MS.

For comparison, the BBRC for the parent drug galantamine was alsodetermined. As demonstrated in the figure, the studied pro-galantaminesall display larger BBRCs than galantamine, with a particularly largeBBRC for Gln-1062 Memogain gluconate is highly water soluble and has noburning sensation to nose, or any taste or smell. Intranasal dosing canbe done with simple spray-pump methods, although also many other methodscan be used. As Memogain is a pharmacologically inactive precursor ofgalantamine and was administered intranasally as gluconate, no GI sideeffects were observed.

Example 8. Memogain Shows Improved Brain Penetration and Low BloodLevels Compared to Galantamine

Data are shown in FIG. 13. Mice were injected with 3 mg/kg i.v. ofeither Memogain or galantamine. The data demonstrate clearly thatgalantamine does not distribute into the brain well (BBRC˜1:1), whereasMemogain has a much higher BBRC (8:1).

Additional data are shown in FIG. 14 for i. n. administration. A Rat PKstudy was carried out with 5 mg/kg intranasal (i.n.) Memogain dosingperformed under GLP-like conditions. The data demonstrate that Memogainhas a much higher BBRC (10:1).

Example 9. Intranasal Memogain is More Potent than Galantamine

To test whether intranasal Memogain is in-vivo a more effectivecognition enhancer than galantamine, the following cognition paradigmwas applied. Mice were treated with scopolamine to induce acute amnesiaand were then tested for performance in a T-maze, in the absence orpresence of oral galantamine or intranasal Memogain (FIG. 7). Clearly,Memogain was more effective than galantamine in reversing the acutelyinduced amnesia. Mice were challenged with Scopolamine i.p. in a T-mazeassay to induce disorientation/amnesia (set to 0% performance recovery).Co-application of galantamine (i.p.) or of Memogain® (i.n.) rescuesorientation in the T-maze in a dose-dependent manner.

Example 10. First Pass Effect of Memogain

The first-pass effect of Gln-1062 was evaluated after intravenous andintraportal dosing of 3 mg/kg in Wistar rats (FIG. 8). Gln-1062 wasobserved to undergo first-pass effect by rapidly decreasing bloodconcentration levels independently of whether it was administered i.v.or i.n. In contrast, the concentration levels of galantamine liberatedfrom Gln-1062 by enzymatic cleavage did not decrease similarly rapidly.Moreover, higher maximal concentration levels of Gln-1062 were observedin brain and blood following i.v administration as compared tointraportal administration. From these data, the first-pass effect wasestimated to be between 35 and 45%.

When Gln-1062 was administered intranasally at the same dose, similarlyhigh maximal concentration levels were observed in the brain as afteri.v. administration, indicating that uptake into the brain was asefficient as after i.v. administration and with little impairment by afirst-pass effect.

Example 11. Intranasal Administration of Memogain Leads to Low Amountsof Liberated Galantamine in Plasma

The study was performed in dogs. A single dose of 4 mg/kg intranasalMemogain was administered and the plasma levels of Memogain andliberated galantamine were determined as a function of time afteradministration. As Memogain is preferentially partitioned into thebrain, only a small fraction of the pro-drug appears in the blood. Thelevels of galantamine liberated from Memogain are much smaller, asgalantamine is rapidly metabolized and excreted (FIG. 9). This leads toa much reduced likelihood of side effects, considering the small amountsof systemic galantamine present in the blood after i. n. administration.

The data from the dog experiments demonstrate:

-   -   Brain:Blood ratio of Memogain (@120 min post administration)=9    -   Brain:Blood ratio of galantamine (@120 min post        administration)=1-1.5    -   Memogain in blood t½=90 min (conscious animals)    -   Galantamine t½=6 h (conscious animals)    -   Low blood levels of galantamine indicates fewer side effects    -   High brain concentrations of Memogain indicate release of        galantamine from Memogain mainly in the brain.

Example 12. Memogain Produces Fewer Gastro-Intestinal Side Effects thanGalantamine

These studies were performed in ferrets that were dosed i.p. with either20 mg/kg galantamine (maximal tolerated dose), or with 20, 40 and 80mg/kg Memogain, respectively. At 20 mg/kg Memogain, no adverse effectswere observed. From the dose dependency of adverse effects, at least 4times lower toxicity in this animal model was observed for Memogain, ascompared to galantamine (FIG. 10).

Similarly, much less adverse effects than observed with galantamine wereseen in the Irwin assay, respiratory toxicity studies, both performed inrats, and in a cardiovascular toxicity study in dogs.

Example 13. Memogain is at Least 10 Times Safer than Galantamine

This study was performed in dogs, and both drugs were administered asintravenous bolus. The lower toxicity of Memogain is due to the muchlower steady-state plasma levels of galantamine resulting from enzymaticcleavage of the pro-drug (FIG. 11).

Medical Benefits of Galantamine Pro-Drugs and their Formulations forTransmucosal Delivery to the Nasal and Buccal Cavity:

The key benefits are as follows:

1. Higher bioavailability and higher effectiveness in the target organ

2. Lower levels of peripheral side effects

3. Pharmacokinetics can be adjusted to medical needs (sustaineddelivery)

4. Dosing not limited by GI adverse effects

5. Faster and stronger onset of medical benefit

6. Up-titration of dose (to enhance compliance) not needed

7. Immediate administration of efficacious doses

8. Improved patient compliance

Higher bioavailability in the brain and higher effectiveness as acognition enhancer was demonstrated by pharmacodynamics studies usingsuitable cognition paradigms in animal models of cognitive impairment.Dramatically lowered incidences of gastro-intestinal adverse effects,i.e. retching and emesis, were shown for intranasal delivery of Memogainin comparison to oral administration of identical doses of Memogain orgalantamine. For intranasal delivery of the pro-galantamine Memogain,even at very high doses, GI-related side effects had practicallydisappeared, as the combined result of better brain penetration of thelipophilic pro-drug and avoidance of the gastro-intestinal tract duringdrug delivery.

In summary, the oral administration of Memogain and galantamine providecomparable BBB-penetration due to the rapid cleavage of Memogain (togalantamine) post-administration. The Memogain salts provide nonoticeable enhanced effect when administered orally at the sameconcentration.

Intravenous administration (i. v.) of Memogain compared to galantaminedemonstrates a vastly improved BBB-penetration for Memogain due to itsmore hydrophobic nature. The i. v. administration of galantamineprovides only a very minor (if any) advantage in comparison to oraldelivery of galantamine, as the active compound itself is relativelystable when compared to Memogain and is not susceptible to esterasecleavage.

Transmucosal administration (intranasal; i. n.) reveals unexpectedenhanced effects with respect to Memogain, and particularly the salts ofMemogain. The i. n. administration of the salts of Memogain show furtherimproved BBB-penetration.

Brain penetration of galantamine is not enhanced by i. n. administrationof galantamine, as the hydrophilic nature of the molecule prohibitseffective penetration regardless of administration route. The i. n.administration of galantamine may avoid some common side effects(Leonard et al (2007)) of galantamine by avoiding administration throughthe digestive tract. The efficacy as cognition enhancer of the moleculeis however not enhanced due to the remaining poor BBRC.

What is claimed is:
 1. A method of treating a subject for a braindisease associated with cognitive impairment, comprising administeringto the subject a therapeutically effective amount of GLN 1062 or saltthereof in a multi-layered tablet with a digestive acid resistantcoating.
 2. The method according to claim 1, wherein the digestive acidresistant coating comprises a poly(meth)acrylate coating.
 3. The methodaccording to claim 1, wherein the tablet comprises a tablet core,wherein said core comprises a therapeutically effective amount of GLN1062 or salt thereof, microcrystalline cellulose (MCC), corn starch,hydroxypropyl methylcellulose (HPMC), and magnesium stearate.
 4. Themethod according to claim 1, wherein the tablet comprises a tablet core,wherein said core comprises microcrystalline cellulose (MCC), andwherein the tablet comprises an active pharmaceutical ingredient layer(API layer) comprising a therapeutically effective amount of GLN 1062 orsalt thereof and hydroxypropyl methylcellulose (HPMC).
 5. The methodaccording to claim 1, wherein GLN1062 is administered as a salt.
 6. Themethod according to claim 4, wherein the salt comprises stoichiometricand/or non-stoichiometric salts and/or hydrates of GLN 1062, whereby thesalt is described as: GLN 1062·n HX·m H2O; wherein n, m=0-5 and n and mcan be the same or different, and HX=an acid.
 7. The method according toclaim 4, wherein the GLN1062 salt has a solubility in water of at least10% weight per volume (w/v).
 8. The method according to claim 4, whereinthe GLN1062 salt is a gluconate salt, saccharate salt, maleate salt, orlactate salt.
 9. The method according to claim 1, wherein GLN1062 orsalt thereof is administered at a dosage of 1 to 100 mg one to threetimes daily.
 10. The method according to claim 1, wherein the braindisease to be treated is selected from the group consisting ofAlzheimer's disease, Parkinson's disease, dementia, schizophrenia,epilepsy, stroke, poliomyelitis, neuritis, myopathy, oxygen and nutrientdeficiencies in the brain after hypoxia, anoxia, asphyxia, cardiacarrest, chronic fatigue syndrome, poisoning, anaesthesia, spinal corddisorders, central inflammatory disorders, postoperative delirium,subsyndromal postoperative delirium, neuropathic pain, abuse of alcoholand drugs, addictive alcohol and nicotine craving, and effects ofradiotherapy.
 11. A method of treating a subject for a brain diseaseassociated with cognitive impairment, comprising administering to thesubject a therapeutically effective amount of GLN 1062 or salt thereofvia transmucosal administration, selected from intranasal, sublingual orbuccal administration, in an emulsion or self-microemulsifying drugdelivery (SMEDD) system.
 12. The method according to claim 11, whereinthe emulsion or SMEDD comprises additionally one or more surfactants,oils and co-surfactants and is prepared under stirring and/orultrasound.
 13. The method according to claim 11, wherein the emulsionor SMEDD comprises additionally glyceryl caprylate, polyethyleneglycol,propyleneglycol and/or diethyleneglycolemonoethylether.
 14. The methodaccording to claim 11, wherein GLN1062 is administered as a salt. 15.The method according to claim 14, wherein the salt comprisesstoichiometric and/or non-stoichiometric salts and/or hydrates of GLN1062, whereby the salt is described as: GLN 1062·n HX·m H2O; wherein n,m=0-5 and n and m can be the same or different, and HX=an acid.
 16. Themethod according to claim 14, wherein the GLN1062 salt has a solubilityin water of at least 10% weight per volume (w/v).
 17. The methodaccording to claim 14, wherein the GLN1062 salt is a gluconate salt,saccharate salt, maleate salt, or lactate salt.
 18. The method accordingto claim 11, wherein GLN1062 or salt thereof is administered at a dosageof 1 to 100 mg one to three times daily.
 19. The method according toclaim 11, wherein the brain disease to be treated is selected from thegroup consisting of Alzheimer's disease, Parkinson's disease, dementia,schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy,oxygen and nutrient deficiencies in the brain after hypoxia, anoxia,asphyxia, cardiac arrest, chronic fatigue syndrome, poisoning,anaesthesia, spinal cord disorders, central inflammatory disorders,postoperative delirium, subsyndromal postoperative delirium, neuropathicpain, abuse of alcohol and drugs, addictive alcohol and nicotinecraving, and effects of radiotherapy.
 20. A method of treating a subjectfor a brain disease associated with cognitive impairment, comprisingadministering to the subject a therapeutically effective amount of GLN1062 or salt thereof via transmucosal administration, selected fromintranasal, sublingual or buccal administration, in a micronized powderformulation.
 21. The method according to claim 11, wherein themicronized powder formulation comprises nanocrystals of GLN 1062 andpolymeric micro-particles to which GLN 1062 is adsorbed.
 22. The methodaccording to claim 11, wherein the micronized powder formulation isobtained by co-precipitation of polymer and GLN 1062, by pearl millingand homogenization in water.
 23. The method according to claim 11,wherein GLN1062 is administered as a base.
 24. The method according toclaim 1, wherein GLN1062 or salt thereof is administered at a dosage of1 to 100 mg one to three times daily.
 25. The method according to claim1, wherein the brain disease to be treated is selected from the groupconsisting of Alzheimer's disease, Parkinson's disease, dementia,schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy,oxygen and nutrient deficiencies in the brain after hypoxia, anoxia,asphyxia, cardiac arrest, chronic fatigue syndrome, poisoning,anaesthesia, spinal cord disorders, central inflammatory disorders,postoperative delirium, subsyndronal postoperative delirium, neuropathicpain, abuse of alcohol and drugs, addictive alcohol and nicotinecraving, and effects of radiotherapy.